Modeling cocaine-induced alterations in organization and patterning of neocortical development using human pluripotent stem cells

Abstract

Disorders of human neocortical development are particularly difficult to study by using animal models because of the marked complexity and unique features of the human cerebral cortex. Developmental effects of cocaine, as well as other drugs and toxins, are particularly challenging to study due to complicating factors such as variations in genetic background, time of exposure, and exposure to multiple substances. Studies aimed at elucidating the effects of cocaine on fetal brain development have used rodent cell lines, primary human cells, and rat models to show that cocaine metabolism by cytochrome P450 results in oxidative ER stress and subsequent impairment of neural progenitor cell proliferation. Recently, in vitro models of neocortical development have been generated by using pluripotent stem cells. One such model, utilizing human pluripotent stem cells, reproduced the formation of neocortical glutamatergic and GABAergic neurons on radial glial scaffolding structure in a temporally sensitive manner mimicking human in vivo neocortical development. Cocaine exposure resulted in the accumulation of reactive oxygen species (ROS), premature neuronal differentiation, accelerated generation of deep-layer and upper-layer glutamatergic projection neurons, and increased formation of GABAergic interneurons. Each of these changes was inhibited by the cytochrome P450 inhibitor cimetidine. These studies suggest that, in the developing human cerebral cortex, cocaine metabolism through cytochrome P450-dependent ROS generation leads to premature neuronal differentiation of neocortical progenitors and impaired neocortical patterning.